2013/05/28 1

Induction Agents

2013/05/28 2

Basic concepts

� One arm-brain circulation time

� Compartments

� Protein binding

� Redistribution vs. Metabolism

� Receptor binding

2013/05/28 3

One arm-brain circulation time

� From introduction into circulation

� ↓

� Pharmacological effect on target organ

2013/05/28 4

One arm-brain circulation time

� Prolonged by

– Decreased cardiac output

– Old age

– Hypothermia

� Clinical implication:

– Inject slowly – wait for effect

Compartments

2013/05/28 5

2013/05/28 6

Compartments

� Blood supply → distribution

� IV induction agent

– Vessel rich group – (brain, heart, kidney, liver)

– Muscle

– Fat

– Bone

2013/05/28 7

Protein binding

� All induction agents - high protein binding

– (>75% except ketamine -12%)

� Active drug = free fraction

– Low protein/albumin = increased free fraction

� Overdose!!!!

� Clinical implication:

– Half the calculated dose, inject slowly

Redistribution

2013/05/28 8

2013/05/28 9

Redistribution vs. Metabolism

� Redistribution

– From one compartment to another

– Decreased [] in vessel rich group

– Arousal → hang over effect

� Metabolism

– Inactivation, breakdown in organ systems

– Elimination via renal, GIT

2013/05/28 10

Receptor binding

� GABAA agonists

– Cl- channel openers

– Inhibitory effect on exitation

� NMDA antagonists (Ketamine)

– Ca2+ channel blocker

2013/05/28 11

Ideal induction agent

� Safe

� Easy to use

� Cheap

� No / minimal cardiovascular effects

� Rapid distribution and metabolism

� No active metabolites

� Analgesia

2013/05/28 12

Ideal induction agent (cont’d)

� No allergic reactions

� No pain upon administration

� No involuntary movements

� No nausea and vomiting

2013/05/28 13

Classification

� Barbiturates - Sodium thiopentone

- Methohexital

� Non-barbiturates - Etomidate

- Propofol

- Ketamine

- Benzodiazepines

2013/05/28 14

STP “Pentothal”

2013/05/28 15

STP “Pentothal”� Synthesized by Lundy in 1932 / 1934

� Pearl Harbour as sole agent � killed many

� Ultra-short acting thiobarbiturate

� Sulphur analogue of pentobarbitone

� Yellow powder, garlic smell, bitter taste

� Preparation: 2,5% = 25mg/ml (500mg/20ml)

� 85% plasma protein binding (albumin)

� 10-15% per hour metabolised by liver

2013/05/28 16

STP “Pentothal”

� Free (unionised) fraction crosses BBB

� Barbiturates are inherently acidic

� Dissolved STP pH = 10,5

– due to added 6% Sodium Carbonate

� Acidosis � excess H+

2013/05/28 17

STP “Pentothal”

� Acidosis � excess H+

Acidic drugs will ionize less

↑↑↑↑ Unionized fraction

↑↑↑↑ Fraction to cross BBB

2013/05/28 18

STP “Pentothal”� Induction agents = lipid soluble

↑ lipid solubility � ↑ plasma protein binding

eg. STP / Methohexitone = 85% Propofol 95%

↓↓↓↓ plasma proteins

↑↑↑↑ free fraction

↑↑↑↑ fraction available to cross BBB

2013/05/28 19

STP “Pentothal” (cont’d)CNS

� Induction in one arm-brain circulation time

� Anticonvulsant

� Anti-analgesic in small dose

� Decreases intracranial pressure

- ↓ CBF

- ↓ CSF production

- ↓ CMRO2

2013/05/28 20

STP “Pentothal” (cont’d)CNS

� Degree of cerebral protection in area of

focal ischaemia if administered before the

ischaemic insult

� Does not protect against global ischaemia

� ↓ intraocular pressure

2013/05/28 21

STP “Pentothal” (cont’d)

RESPIRATORY

� Sensitizes the upper airway

– (compared with Propofol)

� Apnoea 2-3 min

2013/05/28 22

STP “Pentothal” (cont’d)

CVS

� ↓BP � vasodilation + myocardial depression

� Be careful in FIXED CARDIAC OUTPUT!

� Intra-arterial injection

� Extravenous injection

never use stronger than 2,5% STP

2013/05/28 23

STP “Pentothal” (cont’d)INTRA-ARTERIAL INJECTION:

– BURNS / DELAYED OR ABSENT INDUCTION

– Stop injecting!

– Don’t remove the canula!

– Flush with IV fluids Dilute STP

– Lignocaine ↓ Burning

– Heparin Prevent thrombosis

– Brachial plexus block Vasodilation

– Papaverine Vasodilation

2013/05/28 24

STP “Pentothal” (cont’d)EXTRAVENOUS INJECTION:

– BURNS!!

– Stop injecting!

– Not as harmful as intra-arterial injection

– May cause local ulceration if > 2,5%

2013/05/28 25

STP “Pentothal” (cont’d)

� Absolute contraindications

– Porhyria variegata

– Airway obstruction

– Fixed cardiac output

– Severe shock

� Relative contraindications

– Atopic asthma

– Severe liver disease, anaemia

– Myxoedema

2013/05/28 26

PROPOFOL“MILK OF AMNESIA”“MILK OF AMNESIA”“MILK OF AMNESIA”“MILK OF AMNESIA”

2013/05/28 27

PROPOFOL

� 2,6 di-isopropylphenol

� Highly lipid soluble

� Emulsion: - soybean oil

- egg phosphatide

- glycerol

� Excellent medium for Candida

� Feeling of well-being (addiction)

� Erotic feelings!

2013/05/28 28

PROPOFOL (cont’d)

� CVS

– ↓ BP by 30-40%

– No tachycardia!

� RESPIRATORY

– Apnoea if injected fast

– ↓ Sensitivity of upper airway

2013/05/28 29

PROPOFOL (cont’d)

� BURNING

– large vein

– fast running drip

– Lignocaine

� 10mg in 20ml Propofol

� 1mg IV before Propofol

– Opioid

– “Lipuro” – medium chain fatty acids

2013/05/28 30

PROPOFOL (cont’d)

Too good to be true?� No hangover / accumulation

� Anti-emetic

� Anxiolytic

� Amnesia

� Anti-pruritus

� VIAGRA-IN-A-VIAL…!

2013/05/28 31

PROPOFOL (cont’d)

� Ideal agent for TIVA

� Ideal agent for Conscious Sedation

� Ideal agent for placement of LMA

� Excitatory phenomena - myoclonus

- opisthotonus

2013/05/28 32

PROPOFOL (cont’d)

� PROPOFOL INFUSION SYNDROME (PRIS)

CLINICAL FEATURES OF PRIS

1. Sudden onset of marked bradycardia / complete heart block

that is resistant to treatment

2. Lipaemic plasma

3. Hepatomegaly

4. Metabolic acidosis (base deficit > 10 mmol/l)

5. Rhabdomyolysis & Myoglobinuria

6. Multi-organ failure

2013/05/28 33

PROPOFOL INFUSION

SYNDROME (PRIS)

�PATHOGENESIS:– Blockade of L-CAT - ↓ FFA transfer

– ↓ mitochondrial O2 utilization

– ↓ fatty acid β oxidation

– ↓ APT production

– ↑ FFA in blood

2013/05/28 34

PROPOFOL (cont’d)

�TREATMENT:

� Prevention � keep Propofol infusion rate < 4mg/kg/h

and for not more than 24 hour

� Dialysis / plasmapheresis

� Pacemaker

�

PROPOFOL Side effects

� Burns on injection

� Drops BP by 30-40%

� Myoclonus

� Apnoea for 30 sec

� PRIS

2013/05/28 35

2013/05/28 36

ETOMIDATE

2013/05/28 37

ETOMIDATE

� Carboxylated imidazole

� Protein binding = 75%

� EEG ≈ grand mal epilepsy

� ↑Cough and hiccoughing

� Burns

� Thrombophlebitis

� ↑ PONV

� Myoclonus

2013/05/28 38

ETOMIDATE

BRAND / BURNS

BEWE / MYOCLONUS

BRAAK / NAUSEA

BYNIER / ADRENALS

BAIE DUUR / VERY EXPENSIVE

UNWANTED EFFECTS OF ETOMIDATE

2013/05/28 39

ETOMIDATE (cont’d)

� Adrenal cortex inhibition

2013/05/28 40

ETOMIDATE (cont’d)

� Adrenal cortex inhibition

- 11β-hydroxilase inhibition (and 17α-)

- Lasts for 8 h after single bolus

- Vitamin C restores cortisol to normal levels

� NB: Problem with TIVA and single shot induction!

� Hypnotic [ ] = 200nM/ml

� Adrenal suppression [ ] = 10nM/ml

2013/05/28 41

ETOMIDATE (cont’d)

� Remarkable :

- CARDIOVASCULAR STABILITY!

(Alteration in BP, pulse rate negligible)

� Indicated for:

– IHD, hypertensive disease

– Valvular disease

– Cardiac surgery

2013/05/28 42

KETAMINE

� Phencyclidine derivative

� Related to LSD

(lysergic acid diethylamide)

2013/05/28 43

KETAMINE (cont’d)

� What makes KETAMINE different?

– Analgesic

– Cataleptic state

– Dissociation

– Nystagmus

– Protects airway reflexes to certain extend?

– Increased lacrimation, salivation, skeletal muscle tone

2013/05/28 44

KETAMINE (cont’d)

� What makes KETAMINE different?

– Acts on NMDA receptors (antagonist)� protective

– ↑CMRO2, ICP, IOP

– Petit mal activity on EEG

– Hallucinations, delirium, dreams

– Bronchodilator

– Apnoea in very large doses

– Ideal sole anaesthetic agent

2013/05/28 45

KETAMINE (cont’d)

� What makes KETAMINE different?

– ↑ Catecholamine release & ↓ re-uptake:

� ↑ BP

� ↑ Pulse rate

BUT � Direct myocardial suppression

2013/05/28 46

KETAMINE (cont’d)

� What makes KETAMINE different?

↑↑↑↑ ↑↑↑↑ ↑↑↑↑ Catecholamines

Direct ↓↓↓↓ Myocardium

↑↑↑↑ ↑↑↑↑ BP

↑↑↑↑ ↑↑↑↑ Pulse rate

↑↑↑↑ ↑↑↑↑ CO

2013/05/28 47

KETAMINE (cont’d)

� What makes KETAMINE different?

Myocardial suppression ↓ No release of Catecholamines

↓ BP

↓ Pulse rate

↓ CO

2013/05/28 48

KETAMINE (cont’d)

� What makes KETAMINE different?

Very large therapeutic index!� IV = 1-2mg/kg

� IM = 3-5 mg/kg

� PO/rectal = 5-10mg/kg

2013/05/28 49

KETAMINE (cont’d)

Contraindications for Ketamine:

- Hypertension

- Ischaemic heart disease

- ↑ ICP

- Open eye injury

- Psychiatric problems

- Epileptics

- Aneurisms

- Decompensated shock (NA depleted)

2013/05/28 50

Dexmedetomidine

� Highly selective α2 agonist

� Long T½ = ↑ to reach Css

� Used as infusion

– Bolus 1μg/kg for 10 min

– Constant infusion 0,2-0,7μg/kg

� Registered only for:

– Post cardiac surgery sedation for 24h

2013/05/28 51

Dexmedetomidine

� Advantages

– Sedation

– Analgesia

– No respiratory depression

– Anti-shivering agent

� Disadvantages

– Biphasic blood pressure response

– Followed by severe hypotension

2013/05/28 52

BY THE WAY….

ONE ABSOLUTE CONTRAINDICATION

FOR THE ADMINISTRATION OF ALL

THE INDUCTION AGENTS AND ALL

THE MUSCLE RELAXANTS IS…

2013/05/28 53

BY THE WAY….

…A COMPROMISED AIRWAY!

(……and that includes Ketamine)

2013/05/28 54

BY THE WAY….

ETOMIDATE

+

PROPOFOL